Martin B. Leon, MD

Columbia University Medical Center

Cardiovascular Research Foundation

New York City

TAVR 2015:

A Breakthrough Technology

GOES VIRAL!

Issues and Controversies

Disclosure Statement of Financial Interest

TVT 2015, Chicago, IL; June 4-6, 2015

Martin B. Leon, MD

Within the past 12 months, I or my spouse/partner have had a financial

interest/arrangement or affiliation with the organization(s) listed below.

• Grant / Research Support

• Consulting Fees / Honoraria

• Shareholder / Equity

• Abbott, Boston Scientific, Edwards Lifescience, Medtronic

• Meril Lifescience

• Claret, GDS, Mitralign, Valve Medical

Affiliation / Financial Relationship Company

• Addresses an unmet clinical need or an important area of clinical medicine not well served by current therapies

• Innovative concept and/or novel device, drug, or diagnostic technology

• Must be validated by rigorous evidence-based medicine clinical research

• Must be “generalizable” to the practicing medical community (sufficiently user-friendly)

• Rarely, elevates beyond subspecialty medicine and resonates as a significant socio-medical cultural advance (the “X” factor)

What is a Breakthrough Technology?

Demographics &

Projections

TAVR in 2015

TAVR is Available in More Than 65 Countries Around the World

>200,000 total implants to date

Estimated Global TAVR Procedures

SOURCE: Credit Suisse TAVI Comment –January 8, 2015. Revenue split assumption in 2025 is 45% U.S., 35% EU, 10% Japan, 10% ROW

18,000

Estimated Global TAVR Growth

SOURCE: Credit Suisse TAVI Comment –January 8, 2015. ASP assumption for 2024 and 2025 based on analyst model. Revenue split assumption in 2025 is 45% U.S., 35% EU, 10% Japan, 10% ROW

In the next 10 years, TAVR growth will increase X4!

Global $ TAVR Market Potential ($5B by 2025)

SOURCE: Edwards Lifesciences Investor Conference – Dec 11, 2013; Credit Suisse TAVI Comment –January 8, 2015

TAVR Procedures and $ Market

Source: Wall Street Analyst Reports, Company estimates

TAVR Procedures TAVR $ Market

Estimated US and EU TAVR Sites

10

TAVR “Underutilization” is Largely Driven by Variation in Health Policy and Reimbursement

11

SOURCE: Eurostat, U.S. Census Bureau, Industry estimates

The Majority of US Patients with Severe AS Remain “Untreated” (no SAVR/TAVR)

SOURCE: Nkomo 2006, Iivanainen 1996, Aronow 1991, Bach 2007, Freed 2010, Iung 2007, Pellikka 2005; Bach, D. Prevalence and Characteristics of Unoperated Patients with Severe Aortic Stenosis. J Heart Valve Dis. May 2011. (n=406); Industry estimates

2014

Achievements

TAVR in 2015

• Alternative in High-Risk AS Patients - The

original goal of TAVR, to provide a meaningful

less-invasive alternative for high-risk AS patients,

has been achieved!

TAVR in 2015: Achievements

The severe AS-TAVR Population

• Old…very old…

• Frail…very frail

• Lots of co-morbidities…– Prior CABG (poor LV function)– CKD– Severe COPD– PVD– Chronic AF– Cancer in remission

But still enjoying life !

TAVR Categories(risk is a continuum)

Operable AS patients

TAVR in 2015

TAVR

preferred

Extr

Risk*

* Extreme (prohibitive) risk = “inoperable”

Low

Risk

Surgery (AVR)

irresponsible,

reckless

~65%

Moderate

Risk¿

“equipoise”

~25%

High

Risk

TAVRor

AVR

OK

~10%

Fu

tile

No

Too

Sick

Current TAVR

Clinical Use

• Alternative in High-Risk AS Patients - The

original goal of TAVR, to provide a meaningful

less-invasive alternative for high-risk AS patients,

has been achieved!

• Heart Valve Team Concept - Now embraced as

fundamental to TAVR success (optimal clinical

outcomes and accepted in the clinical community);

but may be challenged and will evolve in the future.

TAVR in 2015: Achievements

2014 ACC/AHA Valve Guidelines

CHOICE of Intervention for AS

Indication for AVR

Surgical AVR (I)

High surgical risk

Low-intermediate surgical risk

Heart Valve Team (I)

TAVR (IIa)

Palliative Care

TAVR (I)

BAV (IIb)

Bridge to SAVR or TAVR

for severe symptoms

Prohibitivesurgical risk

Predicted post-TAVRsurvival > 1 yr

YES NO

2014 ACC/AHA Valve Guidelines

CHOICE of Intervention for AS

Indication for AVR

Surgical AVR (I)

High surgical risk

Low-intermediate surgical risk

Heart Valve Team (I)

TAVR (IIa)

Palliative Care

TAVR (I)

BAV (IIb)

Bridge to SAVR or TAVR

for severe symptoms

Prohibitivesurgical risk

Predicted post-TAVRsurvival > 1 yr

YES NO

• Alternative in High-Risk AS Patients - The

original goal of TAVR, to provide a meaningful

less-invasive alternative for high-risk AS patients,

has been achieved!

• Heart Valve Team Concept - Now embraced as

fundamental to TAVR success (optimal clinical

outcomes and accepted in the clinical community);

but may be challenged and will evolve in the future.

• An Evidence-Based Journey - Rigorous clinical

research methods and numerous studies have

validated clinical indications.

TAVR in 2015: Achievements

VARC - 1 and 2 Consensus Reports

Leon MB, et al. J Am Coll Cardiol 2011;57:253-69Kappetein AP, et al. J Am Coll Cardiol 2012;60:1438-54

Current Status:• Total # of published or accepted for publication

manuscripts = 57

• Total # of presented (or scheduled to be presented )

abstracts = 81

• 60 different first authors/presenters from 24 institutions;

20 different journals

Total number of published or presented

manuscripts and abstracts = 138

(from PARTNER 1 and 2)

The PARTNER Publications Office (PPO)

• Improved Clinical Outcomes - Due to better

patient selection, increased operator experience,

routine use of 3D adjunctive imaging (esp. CTA),

new generation TAVR systems, and strategic post-

operative care plans – reduced peri-procedural

complications.

TAVR in 2015: Achievements

6.3%

5.2%

3.7%4.5%

3.5%

2.2%1.6%

1.1% 1.1%

0%

5%

10%

15%

20%

P1B (TF) P1A (All) P1A (TF) P2B (TF) P2B XT (TF) S3HR (All) S3HR (TF) S3i (All) S3i (TF)

All-Cause Mortality at 30 DaysEdwards SAPIEN Valves (As Treated)

175 344 240 271 282 583 491 1072 947

SAPIEN SXT SAPIEN 3

PARTNER 1 and 2 Trials(Overall and TF Patients)

Strokes (All) at 30 DaysEdwards SAPIEN Valves

6.7%

5.6%

4.1% 4.3%

1.5%

2.6%

0%

5%

10%

15%

20%

P1B (TF) P1A (All) P2B (TF) P2B XT (TF) S3HR (All) S3i (All)

179 344 276 284 583 1076

SAPIEN SAPIEN XT SAPIEN 3

Neurologist evaluations (pre- and post)

PARTNER 1 and 2 Trials(Overall and TF Patients)

TAVR in 2015New performance benchmarks

for high-risk AS patients (@ 30 days)

• All-cause mortality < 3%

• Major (disabling) strokes < 2%

• Major vascular complications < 5%

• New permanent pacemakers < 10%

• Mod-severe para-valvular regurgitation < 5%

• Improved Clinical Outcomes - Due to better

patient selection, increased operator experience,

routine use of 3D adjunctive imaging (esp. CTA),

new generation TAVR systems, and strategic post-

operative care plans – reduced peri-procedural

complications.

• Dramatic Technology Enhancements - Striking

response from the medical device industry to

address shortcomings of early TAVR systems,

coupled with advanced imaging systems and new

accessory devices (sheaths/wires/emb prot, etc).

TAVR in 2015: Achievements

TAVR Systems with CE-Approval (2007-15)

Issues

TAVR in 2015

• Valve Sizing and Positioning – Remains

problematic; complex interplay between the valve,

the anatomy, imaging systems, and the operator’s

ability to precisely implant at the desired location;

affects PVL, annulus rupture, and PPM rates.

TAVR in 2015: Issues

ADVANCE IINew Permanent Pacemaker Rate at 30 Days

CoreValve ADVANCE II Study 31

Base of Cusps

Center Marker

(3 mm)

Acceptable Initial

Center Marker Zone

(6 mm)

Optimal SAPIEN 3 Positioning Based on Current Analysis

Optimal SAPIEN 3 Positioning Based on Current Analysis

Optimal S3 Study (D. Dvir et al)

Optimal Position

(n=66)

Non-Optimal Position

(n=82)

P-value

S3 size (mm) 25.9 ± 2.2 25.9 ± 2 0.86

S3 crimped height (mm) 27.3 ± 2.3 27.3 ± 2.1 0.90

Non-transfemoral

approach

19.7% 23.2% 0.88

Post inflation 0% 7.1% 0.04

Coronary obstruction (%) 0% 0% NA

PM implant (%) 6.7% 18.2% 0.04

Major stroke (%) 0% 1.9% 0.31

Death (%) 0% 4.9% 0.07

PVL ≥ moderate (%) 1.5% 2.4% 0.87

PVL ≥ mild (%) 13.6% 25.6% 0.05

Clinical Outcomes

SAPIEN 3 CTA Sizing StudyPAR Stratified by % Oversizing by Area

19.2

29.9

43.249.7

66.2

44.2

45.7

44.738

29.4

21.2

15.7

8.3 8

3.7

9.6

7.92.3 3.7

0.7

3.8

0.8 1.5 0.61.9

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Severe

Moderate-Severe

Moderate

Mild-Moderate

Mild

None/Trace

Below -5%Between

-5% to 0%

Between

0% to 5%

Between

5% to 10%Above 10%

No annulus rupture!(P. Blanke; PCR 2015)

Fre

qu

en

cy o

f P

AR

[%

]

By Area [%] By Perimeter [%]

≥ Mild-to-Moderate and ≥ Moderate PAR stratified by Oversizing

36.5

24.4

12.1 12.3

4.4

15.4

8.7

3.8 4.3 0.70

5

10

15

20

25

30

35

40

< -5 -5 to 0 0 to 5 5 to 10 ≥ 10

29.3

17

12.3

4.3 4.1

10.98.1

2.6 0.6 0.60

5

10

15

20

25

30

35

40

< -2.5 -2.5 to 0 0 to 2.5 2.5 to 5 ≥5

Undersizing/Oversizing

SAPIEN 3 CTA Sizing Study

• Valve Sizing and Positioning - Remains

problematic; complex interplay between the valve,

the anatomy, imaging systems, and the operator’s

ability to precisely implant at the desired location;

affects PVL, annulus rupture, and PPM rates.

• Minimalist Strategy – Includes percutaneous TF

access, reduced # operators in the room, no GA,

no TEE, no pre-dilatation (and very limited post-

dilatation), no hybrid cath lab/OR, and early

discharge programs; ? equivalent clinical outcomes

and carry-over to lower risk patients.

TAVR in 2015: Issues

I Strongy Favor Selective/Frequent TEE for Most TAVR Procedures!!!

• I don’t want to disengage (dismantle) the Heart Team from routine TAVR

• GA – TEE is generally safe and well tolerated (95% patients extubated in the cath lab)

• I prefer advanced imaging for procedural planning and guidance

• I need advanced imaging (3D-TEE) for accurate diagnosis and management of complications –esp. important in lower risk patients!

When the BP suddenly and unexpectedly drops to 50 mmHg during a TAVR…

BMJ 2003;327:1459–61

Call… 1-800 RTHOMG

• Device vs. Device Conundrums - Significant

technology differences among devices, and

currently, 3 TAVR device vs. device RCTs in the

U.S.; thusfar, no major mortality/stroke differences

between Sapien vs. CV; choice determined by

secondary outcomes and anatomic considerations.

TAVR in 2015: Issues

The Ideal Transcatheter Aortic Valve

Optimal Valve Performance

Minimal Interference with

Surrounding Structures

Simple, Predictable Deployment

Low Complication

Rates

Durable

Low Profile for Transfemoral

Delivery

The Ideal Transcatheter Aortic Valve

MDT Evolut R Edwards Sapien 3

• Device vs. Device Conundrums - Significant

technology differences among devices, and

currently, 3 TAVR device vs. device RCTs in the

U.S.; thusfar, no major mortality/stroke differences

between Sapien vs. CV; choice determined by

secondary outcomes and anatomic considerations.

• Adjunctive Pharmacology - An emerging area of

major importance; poorly standardized, few

meaningful studies and will likely affect patient

outcomes, including strokes (esp. AF patients),

? valve thrombosis, and bleeding concerns.

TAVR in 2015: Issues

TAVI AND CEREBROVASCULAR EVENTSSTORTECKY, WINDECKER. CIRCULATION 2012;126:2921-4

TAVR Adjunct PharmacologyCustomized Patient-Based Therapy

New TAVR Pharmacology Trial

PIs: Dangas, G.Windecker, S.

Cohort-Risk 30d 1 Year 2 Years 3 Years 5 Years

All Stroke

Inoperable (B) 6.7% 11.2% 13.8% 15.7% 14.6%

High Risk (A) 4.6% 6.0% 7.7% 8.2% 10.4%

Major Bleeding

Inoperable (B) 16.8% 24.2% 28.9% 32.0% 33.5%

High Risk (A) 9.3% 15.7% 19.0% 20.8% 26.6%Leon NEJM 2010; Smith NEJM 2010; Kodali NEJM 2012; Makkar NEJM 2012;

Kapadia Circulation 2014; Kapadia Lancet 2015.; Mack Lancet 2015

PARTNER 1A and 1B Stroke and Bleeding over Time

Généreux P. AHA 2014, Chicago

Major Bleeding 2.5x

more Frequent than

Stroke

2,401 Patient Survivors post-TAVR6% Major Bleeding between 30dys -1yr

8.6% if Atrial Fibrillation(median time of occurrence: 132 [71, 230] days)

Major Bleeding between 30dys -1yr:Adjusted Mortality: HR 3.83 (2.62-5.61) p<0.0001

Généreux P. et al. JACC 2014;64; 2605-15

Major Bleeding ~4x

Increase in

Mortality

Controversies

TAVR in 2015

• Crossroads: Expanded Clinical Indications -

Are we poised for a MAJOR expansion in TAVR

indications, including moderate and low-risk

patients, bioprosthetic valve failure, asymptomatic

severe AS, and other scenarios; have we passed

the durability “sniff test” for THV? Will regulatory

agencies or reimbursement delays blunt progress?

TAVR in 2015: Controversies

Expanded Clinical IndicationsA TAVR Crossroads?

PARTNER 5-year FU in Lancet(March, 2015)

All-Cause Mortality

An All-comers Randomized Clinical Trial Comparing Transcatheter with

Surgical Aortic Valve Replacement in Patients with Aortic Valve Stenosis

Hans Gustav Hørsted Thyregod, MD

Dep. of Cardiothoracic Surgery, Copenhagen

University Hospital, Denmark

Nordic Aortic Valve Intervention Trial

(NOTION)

Crossover

SAVR to

TAVR

n=1

Crossover

TAVR to

SAVR

n=1

NOTION: Study Flow

Not implanted

n=2

Died prior to

procedure

n=3

Died prior to

procedure

n=1

AT SAVR

n=134

IMPLANTED

SAVR

n=135

Crossover

TAVR to

SAVR

n=3IMPLANTED

TAVR

n=139

AT TAVR

n=142

ITT TAVR

n=145

All randomized

n=280

ITT SAVR

n=135

NOTION: Death (all-cause), Stroke or MI

at 1 Year (as-treated)A

ll-c

au

se M

ort

ality

MI,

or

Str

oke (

%)

P value (log rank) = 0.26

Months Post-procedure

SAVR

0 1 2 3 4 5 6 7 8 9 10 11 12

TAVR

15.7%

11.3%

6.3%

11.9%

No. at risk:TAVR

SAVR

143

134

133

118

129

115

118

105

15%

20%

10%

5%

0%

NOTION: Aortic Valve Performance

*p<0.001

* *

* *

SAVRTAVR

Eff

ecti

ve O

rifi

ce A

rea (

cm

2)

2.0

2.5M

ean

Gra

die

nt (m

m H

g)

44.9

1.5

1.0

0.5

0.0

43.4

0.7

0.7

8.3

12.2

1.4

1.7 1.7

1.3

12.5

8.6

Baseline 3 Months 12 Months

0

10

20

30

40

50

60

InternationalMulticenterRandomized

TAVR UNLOAD

Trial

Heart FailureLVEF < 50%NYHA ≥ 2

Optimal HF therapy(OHFT)

Moderate AS

R

TAVR + OHFT

OHFT alone

Follow-up:1 month6 months

1 year

ClinicalendpointsSymptoms

EchoQoL

Primary Endpoint

Hierarchical

occurrence of:

• All-cause death

• Disabling stroke

• Hospitalizations

for HF, aortic

valve disease, or

non-disabling

stroke

• Change in KCCQ

Reduced AFTERLOAD

Improved LV systolic

and diastolic function

Who does poorly with surgery?

Who does well with TAVR?

• Crossroads: Expanded Clinical Indications -

Are we poised for a MAJOR expansion in TAVR

indications, including moderate and low-risk

patients, bioprosthetic valve failure, asymptomatic

severe AS, and other scenarios; have we passed

the durability “sniff test” for THV? Will regulatory

agencies or reimbursement delays blunt progress?

• “Fatal” Flaws - Early or late structural valve failure

which may limit TAVR expansion; Is the recent

4D-CT valve leaflet abnormality controversy just a

hiccup or a troubling sign?

TAVR in 2015: Controversies

Valve Leaflet Abnormalities

• 7 days after Edwards Sapien XT 29mm TAVR, leaflet thickening on 4D-cine CT• No symptoms and mean AVG 9 mmHg• Warfarin for 10 wks: complete disappearance of CT and TEE abnormalities

2013

• From Jan 2008 to Sept 2013, among 4266 TAVR cases, 26 patients with THV thrombosis (0.61%); 20 Edwards Sapien/Sapien XT , 6 MDT CoreValve

• Median time from TAVR to imaging findings 181 days• Most common Sx was DOE (65%) and 31% were without Sx• Echo (TTE usually): mean AV gradient 40.5 mmHG, thickened leaflets 77%

and thrombotic mass 23%• Warfarin for 2 mos: 23 (88%) reduced symptoms and improved gradients

Latib A et al. Circ Cardiovasc Interv 2015 Apr 8

Valve Leaflet Abnormalities

Valve Leaflet Abnormalities

Diastole

Systole

Makkarr, et al. 2015

Valve Leaflet AbnormalitiesKnowledge

• Frequency:– Neumann 16/156 = 10.2%– Sondegaard (SAVORY) 10/62 = 15%– Makkar : Portico IDE 22/52 = 40% and

RESOLVE 7/70 = 10%

– TOTAL 55/340 = 16.2%• Subclinical: no evidence of increased gradients,

symptoms, or clinical events (not seen on TTE)• Anticoagulation: suggestive case series indicating

improvement in imaging abnormalities after systemic anticoagulation

Valve Leaflet Abnormalities

Makkarr, et al. 2015

Valve Leaflet AbnormalitiesGaps

• Imaging observations and pathobiology– Ultra-sensitive imaging tool documenting

adaptive biocompatibility responses, OR

– Forme fruste of accelerated valve dysfunction with future clinical consequences

• Treatment thresholds (anticoagulation)– High vs. low; selective vs. universal

– Will require large RCTs to sort out

• Risk + resource consumption vs. benefit– Imaging costs and bleeding risks of anticoagulation

Doctor patient relationship!Routine 4D CT after TAVI

I’m doing great!!But I’m really worried about

my leaflet thickness

Valve Leaflet AbnormalitiesNext Steps

15 min post-TAVI

April 16, 2002; FIM-TAVI; Rouen, FR

TAVI: 10-Year Anniversary

“Outpatient” Same-Day TAVRSacre-Coeur Hospital; Montreal, CN

PhilippeGenereux

PhilippeDemers

DonaldPalisaitis